Apolipoprotein E4 effects in Alzheimer’s disease are mediated by synaptotoxic oligomeric amyloid-β

• DOI: 10.1093/brain/aws127
• Publication Date: 2012-05-27T00:24:54Z
• Authors: Robert M. Koffie; Tadafumi Hashimoto; Hwan-Ching Tai; Kevin R. Kay; Alberto Serrano-Pozo; Daniel Joyner; Steven Hou; Katherine J. Kope...; Matthew P. Frosch; Virginia M. Lee; David M. Holtzman; Bradley T. Hyman; Tara L. Spires-Jones
• Keywords: Apolipoprotein E; Amyloid (mycology); Cognitive Decline

The apolipoprotein E ε4 gene is the most important genetic risk factor for sporadic Alzheimer’s disease, but link between this and neurodegeneration remains unclear. Using array tomography, we analysed >50 000 synapses in brains of 11 patients with disease five non-demented control subjects found that synapse loss around senile plaques correlates burden oligomeric amyloid-β neuropil synaptotoxic oligomerized peptide present at a subset synapses. Further analysis reveals have significantly higher exacerbated compared ε3 patients. Apolipoprotein E4 protein colocalizes enhances synaptic localization by >5-fold. Biochemical characterization shows enriched includes sodium dodecyl sulphate-stable dimers trimers. In mouse primary neuronal culture, lipidated association via mechanism involving receptors. Together, these data suggest co-factor toxicity both increasing its levels directing it to synapses, providing genotype loss, major correlate cognitive decline disease.